This invention relates generally to molecular medicine and, more specifically, to context-activated multifunctional protides.
Treatment of many diseases can be severely limited by suboptimal distribution and/or indiscriminant toxicity of the therapeutic agent, and by resistance of the pathogenic target cells or tissue(s) to the chosen therapeutic drug. Drug resistance is a burgeoning and international problem of daunting concern in the treatment of infectious diseases, cancer, and other medical conditions.
The number of new diagnoses each year of all cancer types combined continues to increase. Although cancer drugs can be effective against metastatic disease, their mechanism of action often leads to the survival of drug-resistant tumors and drug toxicity with fatal consequences to the patient. For example, chemotherapy, while generally an effective treatment against human cancerous diseases, is hampered when the specific tumor cell-type becomes resistant to the chemotherapeutic. Overall, one of the greatest limitations on the efficacy of cancer chemotherapeutic agents is the tendency of cancer cells to develop broad-spectrum resistance to a diverse panel of anti-cancer and cytotoxic drugs. Such multiple drug resistance (MDR) is believed to occur to varying degrees in most cancers, either from the onset of the cancer or on recurrence following chemotherapy.
Like cancer, infectious diseases due to pathogenic bacteria, fungi, protozoa and viruses are leading causes of death worldwide. Moreover, the emergence of drug-resistant forms of these pathogens has created an urgent need for new and more effective approaches and anti-infective agents to combat the growing threat of microbial drug-resistance.
Microbes often become resistant to antibiotics and/or non-antibiotic agents. Many conventional antibiotics retard pathogen proliferation by interacting with and/or entering the microbes and interfering with the elaboration of microbial components or pathways needed for macromolecular metabolism (eg., proteins or nucleic acids), cellular regulation, or reproduction. For example, many conventional antibiotics function by impairing DNA replication or expression, transcription, ribosome function, translation, or cell wall or membrane integrity. The majority of available anti-infective agents inhibit intracellular targets within pathogenic microorganisms. Antibiotic resistance typically involves individual or multiple point mutations that slightly change the structure of the antibiotic target, for example, the cell wall synthetic enzymes or ribosomal subunit proteins, such that the antibiotic is no longer effective. Such a slight change in target structure with no detrimental effect on function can be sufficient to reduce or eliminate antibiotic inhibition of the target, translating to reduced or abrogated efficacy of the anti-infective agent. Other common mechanisms for the rapid development of resistance to conventional antibiotics include, for example, degradation of the antibiotic prior to target inhibition, reduced permeability or access of the antibiotic to its target, and/or increased export of the antibiotic by the resistant organism. Thus, antibiotic resistance can occur by the acquisition of genes encoding enzymes that inactivate agents, modify the target of the agent, or result in impermeability or active efflux of the agent. Improved methods for controlling drug resistance in microbes, in particular, microbes that are highly drug resistant, would be of tremendous benefit.
Thus, there exists a need for therapeutic agents that circumvent or have reduced susceptibility to common mechanisms of drug resistance among pathogenic cells, including agents of infectious disease and cancer. The present invention satisfies this need and provides related advantages as well.